The field of the invention is stabilization of implantable bioprosthetic devices and tissues.
Surgical implantation of prostheses and tissues derived from biological sources, collectively referred to herein as bioprosthetic devices or bioprostheses, is an established practice in many fields of medicine. Common bioprosthetic devices include heart valves, pericardial grafts, cartilage grafts and implants, ligament and tendon prostheses, vascular grafts, skin grafts, dura mater grafts, and urinary bladder prostheses. In the case of valvular prosthetic devices, bioprostheses may be more blood compatible than non-biological prostheses because they do not require anticoagulation therapy.
Bioprosthetic devices include prostheses which are constructed entirely of animal tissue, and combinations of animal tissue and synthetic materials. Furthermore, a biological tissue used in a bioprosthetic device can be obtained or derived from the recipient (autogeneic), from an animal of the same species as the recipient (allogeneic), from an animal of a different species (xenogeneic), or alternatively, from artificially cultured tissues or cells. Irrespective of the source of the tissue, major objectives in designing a bioprosthetic device include enhancement of durability and reduction of biomechanical deterioration in order to enhance the functional endurance of the device.
The material stability of bioprosthetic devices can be compromised by any of several processes in a recipient, including, for example, immune rejection of the tissue, mechanical stress, and calcification. Implantation of biological tissue that is not pre-treated (i.e. stabilized prior to implantation) or is implanted without prior suppression of the recipient""s immune system can induce an immune response in the recipient directed against the tissue. Identification of bioprosthetic tissue as xe2x80x98non-selfxe2x80x99 by the immune system can lead to destruction and failure of the implant. Even in the absence of an immune response, mechanical stresses on implanted tissue can induce changes in the structure of the bioprosthesis and loss of characteristics important to its mechanical function. In addition to these degradative processes, calcification of bioprosthetic tissue (i.e. deposition of calcium and other mineral salts in, on, or around the prosthesis) can substantially decrease resiliency and flexibility in the tissue, and can lead to biomechanical dysfunction or failure. In order to extend the useful life of bioprosthetic devices by improving their mechanical properties and mitigating their antigenic properties, the devices can be treated prior to implantation using a variety of agents. These pre-treatment methods are collectively referred to in the art as fixation, cross-linking, and stabilization.
Glutaraldehyde is the most common stabilizing reagent used for treatment of valvular and other collagen-rich bioprosthetic devices. Glutaraldehyde is a cross-linking agent which has been used for pre-implantation stabilization of tissues, both alone and in combination with a variety of other reagents including diisocyanates, polyepoxide ethers, and carbodiimides. Pre-treatment using glutaraldehyde and, optionally, other reagents, stabilizes implantable tissue with respect to both immune reactivity and mechanical stress by covalently linking proteins and other structures on and within the tissue. Cross-linking of a bioprosthetic tissue can be accompanied by treatment with an additional reagent (e.g. ethanol) to retard post-implantation calcification of the tissue. Use of glutaraldehyde as a stabilizing reagent can accelerate prosthesis calcification and necessitates use of a calcification inhibitor. Known calcification inhibitors include ethanol, aluminum chloride, chondroitin sulfate, and aminopropanehydroxyphosphonate (APD).
A significant need exists for compositions and methods capable of stabilizing bioprosthetic devices and reducing post-implantation calcification. The present invention provides such compositions and methods.
The invention relates to an implantable bioprosthesis comprising proteins cross-linked with a poly-(2-hydroxyorgano)amino moiety. The bioprosthesis can be substituted with (i.e. reacted with a polyepoxy amine compound to yield) the poly-(2-hydroxyorgano)amino moiety at two or more epoxy-reactive moieties of the bioprosthesis, such as a methylthio group, a primary amine group, a phenolic hydroxyl group, a phosphate group, or a carboxyl group. For example, substantially all epoxy-reactive groups at the surface of the bioprosthesis can be substituted with (i.e. reacted such that they are linked by) poly-(2-hydroxyorgano)amino moieties. The bioprosthesis can, for example, be any one of an artificial heart, a heart valve prosthesis, an annuloplasty ring, a dermal graft, a vascular graft, a vascular stent, a structural stent, a vascular shunt, a cardiovascular shunt, a dura mater graft, a cartilage graft, a cartilage implant, a pericardium graft, a ligament prosthesis, a tendon prosthesis, a urinary bladder prosthesis, a pledget, a suture, a permanently in-dwelling percutaneous device, a surgical patch, a coated stent, and a coated catheter. The poly-(2-hydroxyorgano)amino moiety can, for example, be a poly-(2-hydroxypropyl)amino moiety, such as that formed by reacting triglycidyl amine with epoxy-reactive groups of the bioprosthesis.
The implantable bioprosthesis can be one which comprises a biological tissue (e.g. a heart, a heart valve, an aortic root, an aortic wall, an aortic leaflet, a pericardial tissue, a connective tissue, dura mater, a bypass graft, a tendon, a ligament, a dermal tissue, a blood vessel, an umbilical tissue, a bone tissue, a fascia, or a submucosal tissue). Such a tissue can be harvested from an animal (e.g. a human, a cow, a pig, a dog, a seal, or a kangaroo). Alternatively, the implantable bioprosthesis can be one which comprises a synthetic analog of a bioprosthetic tissue.
The proteins of the bioprosthesis can be cross-linked by contacting the bioprosthesis with an polyepoxy amine compound, for example in an aqueous liquid having a pH of about 6 to 10, about 7 to 10, or about 7.0 to 7.4. An exemplary polyepoxy amine compound is triglycidyl amine.
The implantable bioprosthesis can be treated with a second stabilization reagent in addition to the polyepoxy amine compound. For example, the second stabilization reagent can be a glycosaminoglycan-stabilizing reagent (e.g. a carbodiimide), a cross-linking reagent, or a calcification inhibitor (e.g. aluminum chloride).
The invention also includes an implantable bioprosthesis made by contacting an implantable bioprosthesis and a polyepoxy amine compound. The bioprosthesis is thereby stabilized.
In addition, the invention includes a method of stabilizing an implantable bioprosthesis. The method comprises contacting the bioprosthesis and a polyepoxy amine compound in order to stabilize the bioprosthesis.
In another aspect, the invention relates to a composition for stabilizing an implantable bioprosthesis. This composition comprises a polyepoxy amine compound and at least one of a calcification inhibitor, a glycosaminoglycan-stabilizing reagent, and a second cross-linking reagent.